J . Org. Chem. 1 9 8 1 , 4 6 , 3461-3466 those of others33follow this trend. The lack of experimental data for bridged [nlannulene and [nlannulene ions is indicative of the difficulties in attempting to prepare these species. This correlates well with our predictions of low aromatic stability which anticipate problems in .making the annulene ions of both variety.
Acknowledgment. We are thankful to Professors E. Vogel (Cologne),G. Hohlneicher (Cologne),and L. T. Scott (Reno) for very useful discussions about the chemical and physical properties of bridged annulenes. In addition, we thank the referees for their comments. Registry No. 3, 2443-46-1; 3 radical cation, 78037-43-1; 3 radical anion, 35533-21-2; 3 dication, 77984-15-7; 3 dianion, 77966-07-5; 4, 14458-51-6;4 radical cation, 78085-70-8; 4 radical anion, 78085-71-9; 4 dication, 77966-08-6; 4 dianion, 77966-09-7; 5,78038-55-8; 5 radical cation, 78038-56-9; 5 radical anion, 78037-44-2; 5 dication, 68630-17-1; 5 dianion, 77984-14-6; 6, 77965-99-2; 6 radical cation, 77966-00-8; 6 radical anion, 78037-45-3; 6 dication, 77966-10-0; 6 dianion, 7796611-1; 7, 77966-01-9; 7 radical cation, 77966-02-0; 7 radical anion, (65) P. J. Garratt and M. V. Sargent, Adu. Org. Chem., 6, 1 (1969).
3461
78037-46-4; 7 dication, 78018-23-2; 7 dianion, 77966-12-2; 8,7796603-1; 8 radical cation, 77966-04-2; 8 radical anion, 78037-47-5; 8 dication, 77966-13-3; 8 dianion, 77966-14-4; [nlpolyacene (n = l o ) , 91-20-3; [nlpolyacene (n = 14), 120-12-7; [nlpolyacene (n = 18), 92-24-0; [nlpolyacene (n = 22), 135-48-8; [nlpolyacene (n = 26), 258-31-1; [nlpolyacene (n = 30), 258-38-8; [nlannulene (n = lo), 3227-76-7; [nlannulene (n = 14), 2873-14-5; [nlannulene (n = la), 2040-73-5; [nlannulene (n = 22), 3227-79-0; [nlannulene (n = 26), 3332-39-6; [nlannulene (n = 30), 3332-40-9; [nlannulene (n = 10) dication, 59975-80-3; [nlannulene (n = 10) dianion, 59947-29-4; [nlannulene (n = 14) dication, 59975-82-5; [nlannulene (n = 14) dianion, 77984-16-8; [nlannulene (n = 18) dication, 77984-17-9; [nlannulene (n = 18) dianion, 77984-18-0; [nlannulene (n = 22) dication, 77984-19-1; [nlannulene (n = 22) dianion, 77984-20-4; [nlannulene (n = 26) dication, 77984-21-5; [nlannulene (n = 26) dianion, 77984-22-6; [nlannulene (n = 30) dication, 78003-76-6; [nlannulene (n = 30) dianion, 77984-23-7; [nlannulene (n = 10) radical cation, 78037-48-6; [nlannulene (n = 10) radical anion, 78037-49-7; [nlannulene (n = 14) radical cation, 78037-50-0; [n]annulene (n = 14) radical anion, 78037-51-1; [nlannulene (n = 18) radical cation, 78037-52-2; [nlannulene (n = 18) radical anion, 78037-53-3; [nlannulene (n = 22) radical cation, 77966-05-3; [n]annulene (n = 22) radical anion, 78037-54-4; [nlannulene (n = 26) radical cation, 77966-06-4; [nlannulene (n = 26) radical anion, 78037-55-5; [nlannulene (n = 30) radical cation, 78037-56-6; [n]annulene (n = 30) radical anion, 78037-57-7.
Reactions of Nitrosoureas and Related Compounds in Dilute Aqueous Acid: Transnitrosation to Piperidine and Sulfamic Acid Sandra S. Singer* and Barbara B. Cole Chemical Carcinogenesis Program, Frederick Cancer Research Center, Frederick, Maryland 21 701 Receiued February 20, 1981
The transnitrosation reactions of four classes of nitrosamides in dilute aqueous acid were studied. Trialkyl nitrosoureas and nitrosoguanidines were found to react very rapidly in transnitrosations to piperidine, giving high yields (7&90%) of nitrosopiperidine at pH 1.7 (perchloric acid) or pH 3.3 (formate buffer). Methylnitrosourea reacted more slowly than either the trialkylnitrosoureas or the nitrosoguanidines and gave moderate yields (48%) of nitrosopiperidine a t pH 1.7 and low yields (6%) at pH 3.3. Nitrosourethanes gave high yields a t pH 1.7 and moderate yields at pH 3.3. Denitrosation rates (transnitrosation to a nitrite trap) are given for a series of monoalkyland trialkylnitrosoureas. An increase in the size of the alkyl group at N1 decreased the rate of denitrosation. The kinetics of nucleophile-catalyzed transnitrosation from trialkylnitrosoureas to piperidine a t pH 1.7 for a series of four trialkylnitrosoureas have been studied. Both the denitrosation of the donor and the nitrosation of the recipient were studied with respect to thiocyanate ion concentration. The denitrosation step was affected only at high [SCN-I, while the nitrosation step showed a first-order dependence on thiocyanate at most concentrations, with a “leveling off’ effect observed at high [SCN-]. The denitrosation step does not exhibit a true dependence on thiocyanate concentration but merely reflects the rapid rate of the nitrosation of the recipient piperidine a t high [SCN-] as a consequence of mass action. The behavior of nitrosoureas in transnitrosation reactions is compared with that of alicyclic nitrosamines. The latter differ from nitrosoureas in that they react more slowly, require a nucleophilic catalysis a t the denitrosation step, and do not always nitrosate strongly basic amines.
The ability of a nitrosamine to act as a nitrosating agent (i.e., to effect transnitrosation) has been demonstrated for aromatic nitrosamines,’V2 which can react via direct and indirect mechanisms, in organic and aqueous media.3 Many aliphatic nitrosamines will transnitrosate under mild conditions in dilute aaueous acid with nucleophilic catalysts.415 (1) Baumgardner, C. L.; McCallum, K. S.; Freeman, J. P. J . Am. Chem. SOC.1961,83, 4417-4419. (2) Sieper, H . Chem. Ber. 1967,100, 1646-1654. (3) Buglass, A. J.; Challis, B. C.; Osborne, M. R. IARC Sci. Publ. 1974, 9. 94-100. (4) Singer, S. S.; Lijinsky, W.; Singer, G. M. Tetrahedron Lett. 1977, 1613-1616. (5) Singer, S. S.; Singer, G. M.; Cole, B. B. J. Org. Chem. 1980, 45, 4931-4935.
0022-3263/81/1946-3461$01.25/0
Nitrosamides are less stable than nitrosamines in acids6 While much is known about the potential alkylating ability of nitrosamides in base via alkyl diazonium ion formation, the acid hydrolysis reactions and, in particular, the nitrosating ability of nitrosoureas have received little attention. Challis and co-workers studied the denitrosation and deamination reactions of N-nitrosopyrrolidone’ and N-butyl-N-nitrosoacetamide?and Williams has studied the denitrosation reactions of 1-methyl-1-nitroso-ptoluenes~lfonamide.~In both cases, proton transfer from (6) Preussmann, R.; Schaper-Druckrey,F. IARC Sci. Publ. 1971,3,81. (7) Challis, B. C.; Jones, S. P. J . Chem. Soc., Perkin Trans. 2 1975, 153-160. (8) Berry, C. N.; Challis, B. C. J . Chem. Soc., Perkin Trans. 2 1974, 1638-1644.
0 1981 American Chemical Society
3462 J . Org. Chem., Vol. 46, No. 17, 1981
Singer and Cole
Chart I CH3
F1
- N-C-N, I NO
,CH3 CH3
1,3,3-lrimelhyII-nitrosourea (TMNU)
1 -ethyl-l-nitroso-3.3-
dimethylurea (EDMNU)
Table I. Transnitrosation to Sulfamic Acid a t pH 1.5a
?
CH3-N-C-N:
I
NO
CH2CH3 CH2CH3
1-methyl-I -nitroso-3,3-
dielhylurea (MDENU)
1.3.3-triethyl-I -nitrosourea (TENU)
solvent was the rate-limiting step; the denitrosation was unaffected by nucleophilic catalysts. Hallett and Williams recently reported a study of the kinetics and mechanism of nitrosation and denitrosation of nitrosomethylurea (NMU) including the effects of nucleophilic catalysts on these reactions.1° Their results are in accord with earlier work on nitros amide^^-^ and clearly show that nitrosation and the reverse reaction of methylurea are first order in acid, methylurea, and nitrite and are not catalyzed by nucleophiles. They offer an explanation for these results based on an analysis of the individual steps in each reaction with the application of a limiting condition to both the forward and the reverse reactions.'O The appearance of nitrous acid in denitrosation experiments was followed by trapping freed nitrous acid with p-chloroaniline and quantitating the coupling product formed with 3-hydroxynaphthalene-2,7-disulfonic acid. The results showed that formation of HNOz was almost complete at acidities ranging from 1.07 to 2.69 M H2S04;Le., under these conditions denitrosation was the only reaction; no deamination or other hydrolysis reactions occurred. Snyder and Stock" have reported on both acid- and base-catalyzed decompositions of l-methyl-l-nitrosourea (NMU) and sym-dimethyl- and 1,3,3-trimethylnitrosourea (TMNU)12in aqueous solutions (see Chart I). The acidcatalyzed decompositions of the mono- and trialkylnitrosoureas differed considerably. Denitrosation was the principal reaction of l-methyl-l-nitrosourea (NMU) at pH
